US9399013B2 - Stable aqueous suspension - Google Patents
Stable aqueous suspension Download PDFInfo
- Publication number
- US9399013B2 US9399013B2 US12/301,053 US30105307A US9399013B2 US 9399013 B2 US9399013 B2 US 9399013B2 US 30105307 A US30105307 A US 30105307A US 9399013 B2 US9399013 B2 US 9399013B2
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- US
- United States
- Prior art keywords
- suspension
- meloxicam
- amount
- suspension according
- steroidal anti
- Prior art date
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- 239000007900 aqueous suspension Substances 0.000 title claims description 5
- 239000000725 suspension Substances 0.000 claims abstract description 81
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 14
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 13
- 229920001285 xanthan gum Polymers 0.000 claims abstract description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000011187 glycerol Nutrition 0.000 claims abstract description 12
- 239000000230 xanthan gum Substances 0.000 claims abstract description 12
- 235000010493 xanthan gum Nutrition 0.000 claims abstract description 12
- 229940082509 xanthan gum Drugs 0.000 claims abstract description 12
- 239000000796 flavoring agent Substances 0.000 claims abstract description 9
- 239000007971 pharmaceutical suspension Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 7
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 7
- 239000003765 sweetening agent Substances 0.000 claims abstract description 7
- 239000001962 taste-modifying agent Substances 0.000 claims abstract description 7
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 6
- 229920000881 Modified starch Polymers 0.000 claims abstract description 5
- 239000012062 aqueous buffer Substances 0.000 claims abstract description 5
- 235000013615 non-nutritive sweetener Nutrition 0.000 claims abstract description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 4
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 29
- 229960001929 meloxicam Drugs 0.000 claims description 25
- 239000002245 particle Substances 0.000 claims description 16
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- 241001465754 Metazoa Species 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 6
- 235000010234 sodium benzoate Nutrition 0.000 claims description 6
- 239000004299 sodium benzoate Substances 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 239000006260 foam Substances 0.000 claims description 3
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- 230000001458 anti-acid effect Effects 0.000 claims description 2
- 230000000767 anti-ulcer Effects 0.000 claims description 2
- 239000004599 antimicrobial Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 claims 1
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- 230000003115 biocidal effect Effects 0.000 claims 1
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 abstract description 24
- 235000019640 taste Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- 229960003184 carprofen Drugs 0.000 description 4
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 4
- -1 colourings Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
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- 230000036470 plasma concentration Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000004150 EU approved colour Substances 0.000 description 3
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 206010067482 No adverse event Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229940100692 oral suspension Drugs 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 150000005599 propionic acid derivatives Chemical class 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
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- 206010003246 arthritis Diseases 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
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- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical class OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- the present invention relates to a novel aqueous pharmaceutical suspension for homogeneously suspending at least one non-steroidal anti-inflammatory drug, a method of their production and their use in the treatment of disease, especially inflammatory diseases in humans and animals.
- Such suspensions are liquid systems having solid particles dispersed substantially throughout.
- liquid dosage forms such as liquid suspensions
- a common problem associated with liquid dosage forms, such as liquid suspensions, is the often disagreeable taste of a drug that manifests itself when the drug is in the liquid dosage form.
- flavouring methodologies to mask the unpleasant taste of drugs.
- a flavour can be selected that complements the taste of the preparation, or a flavour with a longer intensity and stronger taste than the drug can be used.
- High levels of sweetening agents are often used to overwhelm bitterness with sweetness.
- the taste buds may also be anesthetized by menthol or mint flavours.
- EP-A-1,066,029 (MetacamTM) describes a complicated suspension for non-steroidal anti-inflammatory drugs that requires the presence of about 0.1 to about 5% by weight of a highly dispersed silicon dioxide and about 0.05 to about 2% by weight of a hydrophilic polymer.
- the suspension can further comprise a flavouring agent and/or a sweetener.
- EP-A-1,520,578 further describes another suspension system for pharmaceuticals that comprises xanthan gum, a swelling agent, such as pregelatinised starch, a surfactant such as polyoxyethylene sorbitan monooleate, an amino polycarboxylic acid or salt thereof such as ethylenediaminetetraacetic acid (EDTA), and optionally a nucleation inhibitor, such as polyvinylpyrrolidone.
- a swelling agent such as pregelatinised starch
- a surfactant such as polyoxyethylene sorbitan monooleate
- an amino polycarboxylic acid or salt thereof such as ethylenediaminetetraacetic acid (EDTA)
- EDTA ethylenediaminetetraacetic acid
- nucleation inhibitor such as polyvinylpyrrolidone.
- taste modifying agents such as sugars, artificial sweetener, flavouring agents and mixtures thereof, can also be present and generally comprise 25 to 50% by weight of the total composition.
- WO-A-2006/061351 further describes a suspension comprising meloxicam suspended in an aqueous glycerol mixture, a thickening agent, one or more taste modifying agents and a buffer system for maintaining the pH in a range from 2 to 4, wherein the suspension is free or essentially free of silicon dioxide.
- the suspensions known in the art all rely on the presence of taste modifying agents such as bulk sweeteners, intense sweeteners, flavouring agents and mixtures thereof to mask the unpleasant taste of the drugs.
- a stable aqueous pharmaceutical suspension comprising a non-steroidal anti-inflammatory drug, an aqueous buffer system, xanthan gum, polyvinyl pyrrolidone and glycerol which is free from complex excipients such as pregelatinised starch, polyoxyethylene sorbitan monooleate, amino polycarboxylic acid like EDTA, microcrystalline cellulose, hydroxypropylmethyl cellulose, silicon dioxide and taste modifying agents selected from the group consisting of bulk sweeteners, intense sweeteners, flavouring agents and mixtures thereof can successfully mask the unpleasant taste of the drug that is present whilst maintaining stability over a long period of time and avoiding sedimentation of the non-steroidal anti-inflammatory drug.
- an aqueous pharmaceutical suspension comprising:
- the present invention further provides a process for the manufacture of the aqueous suspension as defined in any one of the preceding claims, comprising the following steps:
- non-steroidal anti-inflammatory drug is micronised prior to being introduced in step (i) and/or (ii).
- paddle mixing is used in step (v) to bring the non-steroidal anti-inflammatory drug into a stable suspension.
- the present invention provides the stable aqueous pharmaceutical for use as a medicament.
- the present invention provides the use of the stable aqueous pharmaceutical suspension for the treatment of inflammatory or infectious diseases in humans and animals.
- the present invention further provides the use of the stable aqueous pharmaceutical suspension for the manufacture of a medicament for the treatment of inflammatory or infectious diseases in humans and animals.
- FIG. 1 shows the mean plasma levels of meloxicam in dogs following oral administration at a dose rate of 0.2 mg meloxicam/kg bodyweight on 1 occasion.
- a suspension means a liquid system having solid particles dispersed substantially throughout.
- a suspension does not encompass emulsions which are meant to describe liquids suspended within liquid carriers or syrup formulations containing substantially fully dissolved pharmaceutical actives.
- a “particle” may be a crystal, a granule, an agglomerate, or any undissolved solid material. At least 90% of the particles, preferably between 95 to 98% of the particles, have an equivalent diameter of less than 10 microns. The particle size is measured by laser diffraction.
- Non-steroidal anti-inflammatory drugs can be selected from the group comprising of salicylates such as aspirin, methyl salicylate, Diflunisal and amoxiprin; acetaminophen; arylalkanoic acids such as diclofenac, indomethacin and sulindac; propionic acid derivatives (profens) such as ibuprofen, carprofen, naproxen and ketoprofen; N-Arylanthranlic acids (fenamic acid derivatives) such as mefanamic acid, meclofenamic acid and flufenamic acid; oxicams such as piroxicam, sudoxicam, isoxicam and meloxicam; coxibs such as celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib; sulphonanilides such as nimesulide; and non-steroidal anti-inflammatory drugs that have both cyclo-oxygen
- the non-steroidal anti-inflammatory drug is preferably an oxicam, a propionic acid derivative or mixtures thereof. More preferably the non-steroidal anti-inflammatory drug is meloxicam, piroxicam, carprofen, ibuprofen, ketoprofen or mixtures thereof, more preferably meloxicam or carprofen and most preferably meloxicam.
- At least 90% of the particles of the non-steroidal anti-inflammatory drug preferably between 95 to 98% of the particles, have an equivalent diameter of less than 10 microns.
- the particle size is measured by laser diffraction.
- the particles of the non-steroidal anti-inflammatory drug having an equivalent diameter of less than 10 microns can be obtained for example by micronisation or by milling. Preferably the particles are obtained by micronisation.
- the meloxicam is preferably meloxicam with 95 to 99% of particles having an equivalent diameter less than about 10 micron. Even more preferably the meloxicam particles having an equivalent diameter less than about 10 microns are obtained by micronisation.
- the amount of non-steroidal anti-inflammatory drug present in the suspension should be sufficient to provide a therapeutic amount of the active and a convenient dosage unit. Accordingly, the at least one non-steroidal anti-inflammatory drug can be present in an amount of from about 0.1 to about 5% w/v of the suspension, preferably about 0.1 to about 2.5% w/v of the suspension, even more preferably about 0.1% to about 0.5% of the suspension, and most preferably in an amount of about 0.15% w/v of the suspension.
- non-steroidal anti-inflammatory drug can also be used in combination with other drugs such as but not limited to antimicrobials, antibiotics, antivirals, anti-ulcer/anti-acid agents and anti-cancer agents or a combination thereof.
- the non-steroidal anti-inflammatory drug(s) are present in a “unit dose volume” of the aqueous suspension in a therapeutically effective amount, which is in an amount that produces the desired therapeutic response upon oral administration.
- a “unit dose volume” of the aqueous suspension is a convenient volume for dosing the product to a recipient. The dosing directions instruct the recipient to take amounts that are multiples of the unit dose depending on for example the age or weight of the recipient.
- the unit dose volume of the suspension will contain an amount of non-steroidal anti-inflammatory drug that is therapeutically effective for the smallest patient.
- suitable unit dose volumes may include 0.2 mg non-steroidal anti-inflammatory drug/kg body weight.
- the suspension can be dispensed from a suspension dispenser.
- the suspension is preferably foam free during dispensation from a suspension dispenser.
- the pH of the suspension should range from about 3.5 to about 5, preferably from about 3.8 to about 4.2 and most preferably the pH of the suspension will be about 4.
- the suspension is buffered to maintain the pH of the suspension in the desired pH range. Suitable buffers that are not chemically reactive with the other ingredients may be present in an amount sufficient to provide the desired degree of pH buffering.
- the buffer is a sodium orthophosphate buffer or a citrophosphate buffer and most preferably the buffer is a sodium orthophosphate buffer.
- the buffers can be present in an amount of from about 1 to about 4% w/v of the suspension, more preferably in an amount of from about 1.5 to about 2.5% w/v of the suspension.
- Xanthan gum is a high molecular weight natural carbohydrate, specifically a polysaccharide.
- the xanthan gum is a viscosity increasing agent.
- suitable xanthan gums that can be used in the suspension include Rhodigel 80TM, KeltrolTM, KeltrolTM F, KeltrolTM T, KeltrolTM TF, KeltrolTM 1000 and MerezanTM. Rhodigel 80TM is preferred.
- the xanthan gum can be present in an amount from about 0.25 to about 1% w/v of the suspension, preferably from about 0.4 to 0.75% w/v and most preferably in an amount of about 0.4% w/v of the suspension.
- the suspension includes polyvinyl pyrrolidone and glycerol.
- the polyvinyl pyrrolidone is acting as a dispersant and the glycerol as a vehicle density increaser.
- the polyvinyl pyrrolidone can be present in an amount of from about 0.5 to about 10% w/v of the suspension, preferably from about 0.5 to 3.5% w/v of the suspension and most preferably in an amount of from about 1 to about 2.2% w/v of the suspension.
- the glycerol can be present in an amount of from about 0.5 to about 50% w/v of the suspension, preferably from about 10 to about 30% w/v of the suspension and most preferably in an amount of about 15% w/v of the suspension.
- the suspensions may also contain one or more of the following additives: preservatives, colourings, wetting agents, surfactants and electrolytes.
- Preservatives that can be used in the suspensions include benzoic acid and its pharmaceutically acceptable salts, such as sodium benzoate; sorbic acid and its pharmaceutically acceptable salts, such as potassium sorbate; and parabens (such as methyl, ethyl, propyl and butyl p-hydroxybenzoic acids esters).
- benzoic acid and its pharmaceutically acceptable salts such as sodium benzoate
- sorbic acid and its pharmaceutically acceptable salts such as potassium sorbate
- parabens such as methyl, ethyl, propyl and butyl p-hydroxybenzoic acids esters.
- parabens such as methyl, ethyl, propyl and butyl p-hydroxybenzoic acids esters.
- the preservative can be present in an amount of from about 0.02 to about 0.5% w/v of the suspension, preferably about 0.1 to about 0.3% w/v of the suspension and most preferably in an amount of about 0.15% w/v of the suspension.
- Colouring agents may also be incorporated in the suspension to provide an appealing colour to the suspension.
- the colouring agents should be selected to avoid chemical incompatibilities with the other ingredients in the suspension.
- suitable colouring agents include FD&C Red #40, FD&C Blue #1 and FD&C Red #33.
- wetting agents which may be present include sodium lauryl sulphate or docusate sodium.
- surfactants which may be present include sorbitan oleate ester or polyoxyethylene sorbitan fatty acid esters.
- electrolytes examples include sodium chloride, potassium chloride or sodium bicarbonate.
- the stable aqueous pharmaceutical suspension is prepared by micronising the non-steroidal anti-inflammatory drug and then dispersing the micronised non-steroidal anti-inflammatory drug in glycerol.
- Polyvinyl pyrrolidone is dissolved in water to which the xanthan gum is added. This is then stirred until complete dispersion is attained.
- the non-steroidal anti-inflammatory drug is then added to the Polyvinyl Pyrrolidone/xanthan gum mix.
- aqueous buffer and aqueous sodium benzoate are added followed by water q.s. to 100%.
- the suspensions can be used in the treatment of humans and animals against disease.
- the suspensions can be used against inflammatory diseases such as arthritis or infectious diseases like those of the respiratory tract where inflammation plays a major part in the disease pathology.
- composition of the suspension of the current invention is provided in Table 1.
- a pharmacokinetic study to determine the levels of meloxicam in dogs following the oral administration of the 2 formulations of Examples 1a, 1b and MetacamTM 1.5 mg/ml Oral Suspension for Dogs was carried out in order to compare the plasma levels of meloxicam following administration of the 3 articles.
- the pharmacokinetic parameters AUC (area under the concentration/time curve), C max (the maximum concentration), T max (time of maximum concentration), AUMC (area under the moment curve) and t1 ⁇ 2 (terminal half life) were determined.
- Examples 1a and 1b show bioequivalence to MetacamTM. There was also no adverse reaction to the taste or rejection of the suspensions by the dogs.
- the suspension of this invention is substantially foam free during dispension from a suspension dispenser.
- suspension properties of the suspensions of the current invention were evaluated against the current commercially available meloxicam oral suspension MetacamTM.
Abstract
Description
-
- (i) at least one non-steroidal anti-inflammatory drug;
- (ii) an aqueous buffer system;
- (iii) xanthan gum;
- (iv) polyvinyl pyrrolidone; and
- (v) glycerol
wherein the suspension is free from pregelatinised starch, amino polycarboxylic acid, microcrystalline cellulose, hydroxypropylmethyl cellulose, polyoxyethylene sorbitan monooleate, silicon dioxide and taste modifying agents selected from the group consisting of bulk sweeteners, intense sweeteners, flavouring agents and mixtures thereof.
-
- (i) dissolution of polyvinyl pyrrolidone in water;
- (ii) dispersal of the non-steroidal anti-inflammatory drug in glycerol and in the polyvinyl pyrrolidone of step (i);
- (iii) addition of xanthan gum to steps (i) and/or (ii);
- (iv) making to volume with the addition of water; and
- (v) mixing to bring the non-steroidal anti-inflammatory drug into a stable suspension.
TABLE 1 |
Concentration of excipients an as a % of the w/v of |
Meloxicam suspensions Example 1a and Example 1b |
Excipient and Active | ||
content | Example 1a (% w/v) | Example 1b (% w/v) |
Meloxicam (micronised) | 0.15 | 0.15 |
Sodium benzoate | 0.15 | 0.15 |
Glycerol | 15.0 | 15.0 |
PVP | 1.0 | 2.2 |
Rhodigel 80 ™ | 0.4 | 0.4 |
Purified water q.s. to | 100 | 100 |
Buffered | to a pH of 4 | to a pH of 4 |
Manufacture Process
TABLE 2 |
Plasma levels of meloxicam (μg/ml) in dogs following oral administration |
of Example 1a, Example 1b and Metacam ™ 1.5 mg/ml oral suspension |
(EU/2/97/004/003) at a dose rate of 0.2 mg meloxicam/kg bodyweight |
Example 1a | Example 1b | Metacam ™ | |
Plasma Levels | (n = 4) | (n = 4) | (n = 4) |
Cmax (ug/ml) | 0.61 | (+/−0.04) | 0.70 | (+/−0.17) | 0.69 | (+/−0.11) |
Tmax (hours) | 5.38 | (+/−4.72) | 6.88 | (+/−4.13) | 6.50 | (+/−3.42) |
AUC (ug/ml hrs) | 26.82 | (+/−2.24) | 28.98 | (+/−6.38) | 25.43 | (6.88) |
AUMC (ug/ml hr{circumflex over ( )}2) | 912.89 | (+/131.15) | 980.60 | (+/199.1) | 827.92 | (+/199.93) |
MRT (hrs) | 33.94 | (+/−2.31) | 33.95 | (+/−1.15) | 32.78 | (1.43) |
T½ (hrs | 37.71 | (+/−9.65) | 35.93 | (+/−3.75) | 32.17 | (+/−4.15) |
PRODUCT | TASTE | COMMENT | ||
Example 1a (n = 10) | Neutral | Agreeable | ||
Metacam ™ | Very Sweet | Chalky film on tongue | ||
Claims (9)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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GB0610058.0 | 2006-05-19 | ||
GB0610058A GB0610058D0 (en) | 2006-05-19 | 2006-05-19 | Stable aqueous suspension |
GB0610246A GB0610246D0 (en) | 2006-05-23 | 2006-05-23 | Stable aqueous suspension |
GB0610246.1 | 2006-05-23 | ||
GB0708375A GB2438287A (en) | 2006-05-19 | 2007-04-30 | Stable aqueous suspension |
GB0708375.1 | 2007-04-30 | ||
PCT/GB2007/001700 WO2007135362A2 (en) | 2006-05-19 | 2007-05-10 | Stable aqueous suspension having palatable taste |
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US9399013B2 true US9399013B2 (en) | 2016-07-26 |
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US (1) | US9399013B2 (en) |
JP (2) | JP5391063B2 (en) |
KR (1) | KR101452721B1 (en) |
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CR (1) | CR10429A (en) |
DE (1) | DE602007003026D1 (en) |
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PE (1) | PE20080233A1 (en) |
PT (1) | PT2034958E (en) |
SI (1) | SI2034958T1 (en) |
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US20210093642A1 (en) * | 2019-09-26 | 2021-04-01 | Cadila Healthcare Limited | STABLE AQUEOUS PARENTERAL SOLUTIONS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) |
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JP6050564B2 (en) * | 2010-03-11 | 2016-12-21 | テイカ製薬株式会社 | Film-form preparation |
GB201117858D0 (en) * | 2011-10-17 | 2011-11-30 | Norbrook Lab Ltd | Paste |
FI126442B (en) * | 2011-11-01 | 2016-12-15 | Valio Oy | Enzyme preparation in liquid form and process for its preparation |
KR20200046018A (en) * | 2017-08-24 | 2020-05-06 | 지앙수 헨그루이 메디슨 컴퍼니 리미티드 | Pharmaceutical composition for injection containing meloxicam and method for manufacturing the same |
KR102145022B1 (en) * | 2018-08-14 | 2020-08-14 | 동아제약 주식회사 | Suspension composition and dosage form of ibuprofen |
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US20040258716A1 (en) | 2002-06-17 | 2004-12-23 | Shen Gao | Ibuprofen suspension |
US20040229038A1 (en) * | 2003-03-03 | 2004-11-18 | Elan Pharma International Ltd. | Nanoparticulate meloxicam formulations |
EP1520578A1 (en) | 2003-09-30 | 2005-04-06 | McNEIL-PPC, Inc. | Medicinal suspensions |
WO2006061351A1 (en) | 2004-12-06 | 2006-06-15 | Janssen Pharmaceutica N.V. | Oral suspension comprising meloxicam |
Cited By (1)
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US20210093642A1 (en) * | 2019-09-26 | 2021-04-01 | Cadila Healthcare Limited | STABLE AQUEOUS PARENTERAL SOLUTIONS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) |
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EA015301B1 (en) | 2011-06-30 |
EA200870546A1 (en) | 2009-04-28 |
SI2034958T1 (en) | 2010-02-26 |
CR10429A (en) | 2008-12-01 |
GB2438287A (en) | 2007-11-21 |
US20090186883A1 (en) | 2009-07-23 |
ATE446740T1 (en) | 2009-11-15 |
DE602007003026D1 (en) | 2009-12-10 |
KR101452721B1 (en) | 2014-10-21 |
JP2009537495A (en) | 2009-10-29 |
GB0708375D0 (en) | 2007-06-06 |
IL194244A (en) | 2011-12-29 |
KR20090023607A (en) | 2009-03-05 |
PE20080233A1 (en) | 2008-04-10 |
DK2034958T3 (en) | 2010-03-15 |
PT2034958E (en) | 2010-01-04 |
JP5391063B2 (en) | 2014-01-15 |
ES2335622T3 (en) | 2010-03-30 |
MX2008011775A (en) | 2008-10-01 |
NZ572380A (en) | 2011-10-28 |
JP2013241422A (en) | 2013-12-05 |
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